More Than a Gut Feeling: Role of Microbiome in Health, Disease, and Drug Therapy

By Karunya K. Kandimalla and Purna C. Kashyap

The vast collection of microbial life within, on, and around us has established a complex interaction network that influences human health and disease. This realization triggered renewed efforts from the scientific community to unleash knowledge that could open avenues to investigate the pathogenesis of several chronic diseases and identify novel diagnostic and therapeutic strategies. Even if this new excitement and hypotheses are not yet fully perfused with logic and experimental evidence, there are examples describing the influence of microbiome on host physiology, pathobiology, and drug therapy. The most convincing and better investigated of those exist for the gut microbiome,
which is an ecological community of over a trillion commensal, symbiotic, and pathogenic microbes residing in the gastrointestinal (GI) tract.The gut microbiome plays a critical role in extracting nutrients from the ingested food, modulating the risk of severe gastrointestinal infections, and affecting the absorption and metabolism of orally administered drugs. Consequently, the gut microbiome could contribute to individual variations in nutrient assimilation, energy metabolism, and drug therapy.

Alteration of gut microbiota with antibiotics could perturb the intricately balanced gut ecosystem and trigger the colonization of pathogens like Clostridium difficile. Fecal microbiota transplant from a healthy individual was shown to restore the colonization resistance, suppress C. difficile proliferation, and ameliorate the symptoms. A similar paradigm likely holds true for other infections like Salmonella. The gut microbiota also plays an important role in regulating host metabolism. Shifts in the microbial constitution could impair glucose tolerance and result in weight gain. The glucose tolerance in obese people noticeably improved when the gut microbiota was transplanted from lean to obese individuals.

The gut microbiota could affect the absorption and metabolism of orally administered drugs and contribute to individual variations in drug therapy. Studies have shown that gut microbiota modulates the GI mucosal barrier and influences the systemic absorption of orally administered drugs as well as bacterial metabolites. The GI absorption of lipophilic molecules mostly occurs transcellularly across the GI epithelium, but the low molecular weight hydrophilic compounds are absorbed across the paracellular spaces. While the membrane transporters like permeability-glycoprotein (P-gp) and breast cancer related protein (BCRP) limit the transcellular absorption of drugs and bacterial metabolites, the paracellular tight junctions restrict the permeability of hydrophilic molecules. By modulating the expression of membrane transporters and tight junctional proteins, the gut microbiota is believed to alter the drug absorption across the GI mucosa. Similarly, the bacterial metabolites released into the gut could make their way into systemic circulation due to altered mucosal integrity and influence the physiology of distant organs. The gut microbiota could also interfere with the metabolism and clearance of orally administered anticancer drugs like irinotecan. Consequently, microbiota may exacerbate the dose-limiting diarrheal side effects of irinotecan.

It is evident through these examples that gut microbiota play a key role in several functions vital for our health, and we have made huge leaps over the past decade in terms of accelerating microbiome research and translating the early findings. Further inquiries into this long-neglected organ is highly essential to realize the goals of precision medicine.

Karunya Kandimalla is an associate professor in the Department of Pharmaceutics at the College of Pharmacy, University of Minnesota, Minneapolis, MN. He directs the Biopharmaceutics and Systems Physiology program that investigates trafficking/signaling perturbations at the blood/brain and gut interfaces in neurological and metabolic disorders.

Purna Kashyap is an assistant professor in Gastroenterology and Hepatology and Physiology and the associate program director of the Microbiome program within the Center for Individualized Medicine at Mayo Clinic, Rochester, MN. His research program aims to better understand the interaction of diet and gut microbiota in the pathogenesis of functional gastrointestinal disorders.